SOX9

轉錄因子SOX9是一種蛋白質，在人類中由SOX9基因編碼，是塞特利氏細胞等細胞的標誌物。^[5][6]

SOX9
已知的結構 PDB 直系同源搜尋: PDBe RCSB PDBID列表 4EUW
識別號
別名	SOX9；, CMD1, CMPD1, SRA1, SRXX2, SRXY10, SRY-box 9, SRY-box transcription factor 9
外部ID	OMIM：608160 MGI：98371 HomoloGene：294 GeneCards：SOX9
基因位置（人類） 染色體 17號染色體[1] 基因座 17q24.3 起始 72,121,020 bp[1] 終止 72,126,416 bp[1]
基因位置（小鼠） 染色體 小鼠11號染色體[2] 基因座 11 E2|11 77.27 cM 起始 112,673,050 bp[2] 終止 112,678,586 bp[2]
RNA表現模式
查閱更多表現資料
基因本體 分子功能 • DNA結合轉錄因子活性 • DNA-binding transcription activator activity, RNA polymerase II-specific • core promoter sequence-specific DNA binding • 蛋白激酶活性 • protein kinase A catalytic subunit binding • beta-catenin binding • pre-mRNA intronic binding • chromatin binding • 血漿蛋白結合 • DNA結合 • sequence-specific DNA binding • transcription cis-regulatory region binding • bHLH transcription factor binding • 核心啟動子近端區域序列特異性DNA結合 • protein heterodimerization activity • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • DNA-binding transcription factor activity, RNA polymerase II-specific • RNA polymerase II cis-regulatory region sequence-specific DNA binding 細胞組分 • 細胞核 • 轉錄調節錯合物 • 核質 • 大分子複合體 生物學過程 • 骨骼系統的發生 • cellular response to retinoic acid • bronchus cartilage development • positive regulation of protein phosphorylation • heart valve development • limb bud formation • positive regulation of protein catabolic process • regulation of transcription by RNA polymerase II • ureter morphogenesis • negative regulation of immune system process • chondrocyte development • positive regulation of cell proliferation involved in heart morphogenesis • oligodendrocyte differentiation • chondrocyte hypertrophy • prostate gland development • lung smooth muscle development • 乳腺發育 • negative regulation of ossification • negative regulation of photoreceptor cell differentiation • cellular response to mechanical stimulus • intrahepatic bile duct development • regulation of cell adhesion • negative regulation of chondrocyte differentiation • positive regulation of mesenchymal cell proliferation • astrocyte fate commitment • positive regulation of chondrocyte differentiation • 精子發生 • prostate gland morphogenesis • negative regulation of epithelial cell proliferation • lung epithelial cell differentiation • chondrocyte differentiation involved in endochondral bone morphogenesis • negative regulation of canonical Wnt signaling pathway • endocrine pancreas development • negative regulation of cell population proliferation • regulation of apoptotic process • cellular response to transforming growth factor beta stimulus • negative regulation of mesenchymal cell apoptotic process • 染色體重建 • negative regulation of myoblast differentiation • positive regulation of branching involved in ureteric bud morphogenesis • cell fate commitment • regulation of transcription, DNA-templated • epidermal growth factor receptor signaling pathway • 成骨作用 • regulation of cell proliferation involved in tissue homeostasis • ureter smooth muscle cell differentiation • ERK1 and ERK2 cascade • notochord development • positive regulation of epithelial cell migration • Sertoli cell differentiation • male sex determination • negative regulation of gene expression • transcription, DNA-templated • metanephric nephron tubule formation • positive regulation of transcription, DNA-templated • 心臟發育 • regulation of branching involved in lung morphogenesis • ureter urothelium development • branching involved in ureteric bud morphogenesis • 軟骨生成 • Harderian gland development • positive regulation of kidney development • central nervous system development • heart valve formation • positive regulation of cartilage development • tissue homeostasis • metanephric tubule development • negative regulation of biomineral tissue development • endochondral bone morphogenesis • trachea cartilage development • male germ-line sex determination • 淚腺的發生 • Notch信號通路 • hair follicle development • 細胞分化 • 輸尿管的發生 • regulation of cell cycle process • male gonad development • positive regulation of epithelial cell proliferation • cell fate specification • intestinal epithelial structure maintenance • positive regulation of extracellular matrix assembly • extracellular matrix organization • negative regulation of apoptotic process • negative regulation of transcription by RNA polymerase II • Sertoli cell development • positive regulation of mesenchymal stem cell differentiation • retina development in camera-type eye • cellular response to interleukin-1 • 上皮-間充質轉換 • homeostasis of number of cells within a tissue • negative regulation of transcription, DNA-templated • cAMP-mediated signaling • cartilage condensation • positive regulation of male gonad development • nucleosome assembly • negative regulation of bone mineralization • morphogenesis of a branching epithelium • neural crest cell development • Akt/PKB信號通路 • somatic stem cell population maintenance • otic vesicle formation • otic vesicle development • endocardial cushion morphogenesis • cellular response to epidermal growth factor stimulus • positive regulation of epithelial cell differentiation • renal vesicle induction • positive regulation of gene expression • regulation of epithelial cell proliferation involved in lung morphogenesis • regulation of cell population proliferation • heart valve morphogenesis • 細胞骨架組織 • cochlea morphogenesis • positive regulation of cell population proliferation • epithelial cell proliferation involved in prostatic bud elongation • retinal rod cell differentiation • protein localization to nucleus • regulation of cell differentiation • positive regulation of phosphatidylinositol 3-kinase signaling • cellular response to heparin • negative regulation of epithelial cell differentiation • epithelial tube branching involved in lung morphogenesis • 訊息傳遞 • positive regulation of transcription by RNA polymerase II • negative regulation of pri-miRNA transcription by RNA polymerase II • chondrocyte differentiation • neural crest cell fate specification • cellular response to BMP stimulus • cell-cell adhesion • transcription initiation from RNA polymerase II promoter • protein-containing complex assembly • anterior head development • morphogenesis of an epithelium • aortic valve morphogenesis • 基因調節 Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	6662	20682
Ensembl	ENSG00000125398	ENSMUSG00000000567
UniProt	P48436	Q04887
mRNA​序列	NM_000346	NM_011448
蛋白序列	NP_000337	NP_035578
基因位置​（UCSC）	Chr 17: 72.12 – 72.13 Mb	Chr 11: 112.67 – 112.68 Mb
PubMed​查找	[3]	[4]
維基資料
檢視/編輯人類 檢視/編輯小鼠

功能

SOX9識別序列CCTTGAG，與其他HMG-box類DNA結合蛋白一起發揮作用。它由增殖但非肥大軟骨細胞表達，對於前體細胞分化為軟骨細胞至關重要^[7]，並且與類固醇生成因子1一起調節抗苗勒氏激素（AMH）基因的轉錄。^[6]

SOX9也在雄性性發育中扮演著關鍵角色；通過與Sf1協同作用，SOX9可以在賽特利氏細胞中產生AMH，以抑制女性生殖系統的形成。^[8] 它還與其他幾個基因互作，以促進雄性生殖器官的發育。該過程始於轉錄因子睪丸決定因子（由Y染色體的性別決定區SRY編碼）通過結合在該基因上游的一段強化子序列，活化SOX9活性。^[9] 接著，SOX9活化FGF9並與FGF9形成前饋迴路^[10]和PGD2。^[9]

這些迴路對於產生SOX9十分重要；如果沒有這些迴路，SOX9將會耗盡，且幾乎可以確定會出現女性的發育。SOX9活化FGF9啟動男性發育中的重要過程，例如創建睪丸索以及塞特利氏細胞的增殖。^[10] SOX9與Dax1的結合實際上會產生塞爾托利細胞，這是雄性發育中另一個重要的過程。^[11] 在大腦發育中，其小鼠直系同源基因SOX9誘導Wwp1、Wwp2和miR-140的表達，以調節新生神經細胞進入皮質板，並調節皮質神經元的軸突分支和軸突形成。^[12]

Sox9，也被稱為SRY-Box轉錄因子9，是性別決定中一個重要的基因。SOX家族基因全都是Y染色體性別決定因子SRY的轉錄因子。SRY基因編碼SOX轉錄因子，同時它上調Sox9。Sox9之後啟動Fgf9，即成纖維細胞生長因子9，這也是雄性腺體形成過程中的另一個關鍵轉錄因子。Fgf9通過正向前饋級聯上調Sox9，這導致塞特利氏細胞分化，最終形成睪丸。^[13]

SOX9是Notch訊息傳遞途徑以及Hedgehog途徑的標靶，^[14]並在調節神經幹細胞命運中扮演角色。體內和體外研究顯示SOX9對神經元生成具有負調控作用，對膠質細胞生成和幹細胞存活具有正調控作用。^[15]

在成年關節軟骨細胞中，通過siRNA介導的SOX9或RTL3敲低會導致另一個基因的下調，以及II型膠原蛋白（COL2A1）mRNA和蛋白表達的降低。^[16]

在缺乏SRY的情況下，於XY性腺中過度表現SOX9可以進一步促進雄性性別決定和睪丸發育。^[17] 亦可發現，在XX性腺異位表現SOX9，即使在缺乏SRY的情況下亦會導致睪丸的發育。^[18] 這兩者皆證明，SOX9在缺乏SRY的情況下，無論在XX或XY性腺中，仍將持續於睪丸發育、睪丸分化和性別決定上發揮關鍵作用。亦有詳細說明SOX9可替代SRY的功能。^[19][20]

臨床意義

突變會導致骨骼畸形症候群彎骨發育不全，通常伴有體染色體性別反轉^[6]和裂顎。^[21]

SOX9位於人類17q24的基因沙漠中。SOX9兩側距轉錄單位超過1Mb的高度保守非編碼元件的缺失、被易位斷點干擾以及單點突變，都與皮埃爾·羅賓序列相關，且常伴有顎裂。^[21][22]

SOX9蛋白已被認為與多種實質固態瘤(solid tumors)的發生和進展有關。^[23] 其作為形態發生的主調節因子在人體發育過程中的角色，使其成為惡性組織中擾動的理想候選者。具體而言，SOX9似乎在前列腺、^[24]結直腸、^[25]乳腺^[26]和其他癌症中誘導侵襲性和治療抵抗性，從而促進致命的轉移。^[27]SOX9的許多這些致癌效應似乎是劑量依賴的。^[28][24][23]

SOX9 的定位和動態

SOX9 主要定位於細胞核中，且具有高度的流動性。對軟骨細胞系的研究顯示，近50%的 SOX9 與 DNA 結合，並且直接受到外部因素的調控。其在 DNA 上的駐留半衰期約為14秒。^[29]

在性別分化中的角色

SOX9幫助引導SRY在性別分化中的活化。SOX9或任何相關基因的突變可能導致性別逆轉。如果SOX9活化的FGF9不存在，具有X和Y染色體的胎兒將成為女性。^[9] 如果DAX1不存在，情況也是如此。^[11] 相關現象可能由於SRY在XX男性症候群中的不尋常活動引起，通常是當它轉位到X染色體上並且其活動僅在某些細胞中被活化時。^[30] SOX9的突變或缺失可能導致XY胎兒成為女性，因為SOX9是一個關鍵的效應基因，通過SRY基因作用來分化支持細胞並推動男性睪丸的形成。^[13]

相互作用

已顯示SOX9與類固醇生成因子1^[8]、MED12^[31]、MAF^[32]、SWI/SNF、MLL3和MLL4發生相互作用。^[33]

基因剔除模型

SOX9的功能喪失突變可能導致彎曲肢體發育不全症（CD），這是由於影響蛋白質功能的突變和破壞基因表現的易位。已經有SOX9基因剔除小鼠顯示出中風恢復的改善，特別是在抑制如NOGO和硫酸軟骨素蛋白聚醣（CSPGs）等軸突萌芽抑制劑時。SOX9的去除導致CSPG水平降低，這增加了組織保護並改善了中風後的神經恢復。這些SOX9基因剔除小鼠促進修復性軸突萌芽、神經保護和中風後的恢復。^[34]

參見

• SOX基因家族

進一步閱讀

• Ninomiya S, Narahara K, Tsuji K, Yokoyama Y, Ito S, Seino Y. Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation. American Journal of Medical Genetics. March 1995, 56 (1): 31–34. PMID 7747782. doi:10.1002/ajmg.1320560109.
• Lefebvre V, de Crombrugghe B. Toward understanding SOX9 function in chondrocyte differentiation. Matrix Biology. March 1998, 16 (9): 529–540. PMID 9569122. doi:10.1016/S0945-053X(98)90065-8.
• Harley VR. The Molecular Action of Testis-Determining Factors SRY and SOX9. The Genetics and Biology of Sex Determination. Novartis Foundation Symposia 244. 2002: 57–66; discussion 66–7, 79–85, 253–7. ISBN 9780470843468. PMID 11990798. doi:10.1002/0470868732.ch6.
• Kwok C, Weller PA, Guioli S, Foster JW, Mansour S, Zuffardi O, Punnett HH, Dominguez-Steglich MA, Brook JD, Young ID. Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. American Journal of Human Genetics. November 1995, 57 (5): 1028–1036. PMC 1801368 . PMID 7485151.
• Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanović M, Weissenbach J, Mansour S, Young ID, Goodfellow PN. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. December 1994, 372 (6506): 525–530. Bibcode:1994Natur.372..525F. PMID 7990924. S2CID 1472426. doi:10.1038/372525a0.
• Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, Wolf U, Tommerup N, Schempp W, Scherer G. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. December 1994, 79 (6): 1111–1120. PMID 8001137. S2CID 24982682. doi:10.1016/0092-8674(94)90041-8.
• Südbeck P, Schmitz ML, Baeuerle PA, Scherer G. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Nature Genetics. June 1996, 13 (2): 230–232. PMID 8640233. S2CID 22617889. doi:10.1038/ng0696-230.
• Cameron FJ, Hageman RM, Cooke-Yarborough C, Kwok C, Goodwin LL, Sillence DO, Sinclair AH. A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. Human Molecular Genetics. October 1996, 5 (10): 1625–1630. PMID 8894698. doi:10.1093/hmg/5.10.1625 .
• Meyer J, Südbeck P, Held M, Wagner T, Schmitz ML, Bricarelli FD, Eggermont E, Friedrich U, Haas OA, Kobelt A, Leroy JG, Van Maldergem L, Michel E, Mitulla B, Pfeiffer RA, Schinzel A, Schmidt H, Scherer G. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Human Molecular Genetics. January 1997, 6 (1): 91–98. PMID 9002675. doi:10.1093/hmg/6.1.91 .
• Cameron FJ, Sinclair AH. Mutations in SRY and SOX9: testis-determining genes. Human Mutation. 1997, 9 (5): 388–395. PMID 9143916. S2CID 45387678. doi:10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0.
• Wunderle VM, Critcher R, Hastie N, Goodfellow PN, Schedl A. Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proceedings of the National Academy of Sciences of the United States of America. September 1998, 95 (18): 10649–10654. Bibcode:1998PNAS...9510649W. PMC 27949 . PMID 9724758. doi:10.1073/pnas.95.18.10649 .
• De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. Molecular and Cellular Biology. November 1998, 18 (11): 6653–6665. PMC 109250 . PMID 9774680. doi:10.1128/mcb.18.11.6653.
• McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V. Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. The Journal of Biological Chemistry. August 1999, 274 (34): 24023–24030. PMID 10446171. doi:10.1074/jbc.274.34.24023 .
• Huang W, Zhou X, Lefebvre V, de Crombrugghe B. Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Molecular and Cellular Biology. June 2000, 20 (11): 4149–4158. PMC 85784 . PMID 10805756. doi:10.1128/MCB.20.11.4149-4158.2000.
• Thong MK, Scherer G, Kozlowski K, Haan E, Morris L. Acampomelic campomelic dysplasia with SOX9 mutation. American Journal of Medical Genetics. August 2000, 93 (5): 421–425. PMID 10951468. doi:10.1002/1096-8628(20000828)93:5<421::AID-AJMG14>3.0.CO;2-5.
• Ninomiya S, Yokoyama Y, Teraoka M, Mori R, Inoue C, Yamashita S, Tamai H, Funato M, Seino Y. A novel mutation (296 del G) of the SOX90 gene in a patient with campomelic syndrome and sex reversal. Clinical Genetics. September 2000, 58 (3): 224–227. PMID 11076045. S2CID 28618271. doi:10.1034/j.1399-0004.2000.580310.x.
• Preiss S, Argentaro A, Clayton A, John A, Jans DA, Ogata T, Nagai T, Barroso I, Schafer AJ, Harley VR. Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. The Journal of Biological Chemistry. July 2001, 276 (30): 27864–27872. PMID 11323423. doi:10.1074/jbc.M101278200 .